Hypothalamic leptin gene therapy prevents weight gain without long-term detrimental effects on bone in growing and skeletally mature female rats

Iwaniec, Urszula T.; Boghossian, Stéphane; Trevisiol, C.H.; Wronski, Thomas J.; Turner, Russell T.; Kalra, Satya P.

doi:10.1002/jbmr.365

Cited by 22 publications

(16 citation statements)

References 95 publications

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“…These findings are consistent with numerous other studies documenting the efficacy of central leptin gene therapy in attenuating weight gain in various paradigms in rats and mice [2,3,11,22,26]. Hypothalamic leptin gene therapy also modified the expression of hypothalamic genes that regulate body weight, such as NPY, POMC and CART, and systemic levels of hormones and adipokines, such as leptin, insulin, IGF-I, adiponectin, and IL-6 [2,10,12,22,28,47], factors shown to influence bone metabolism [31,46]. Although not assessed in this study, based on the current results it is tempting to speculate that these potential modifications had little or no impact on the skeletal response to ovx.…”

Section: Discussionsupporting

confidence: 92%

Effects of increased hypothalamic leptin gene expression on ovariectomy-induced bone loss in rats

et al. 2011

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Estrogen deficiency results in accelerated bone turnover with a net increase in bone resorption. Subcutaneous administration of leptin attenuates bone loss in ovariectomized (ovx) rats by reducing bone resorption. However, in addition to its direct beneficial effects, leptin has been reported to have indirect (central nervous system-mediated) antiosteogenic effects on bone, which may limit the efficacy of elevated serum leptin to prevent estrogen deficiency-associated bone loss. The present study evaluated the long-term effects of increased hypothalamic leptin transgene expression, using recombinant adeno-associated virus-leptin (rAAV-Lep) gene therapy, on bone mass, architecture, and cellular endpoints in sexually mature ovx Sprague-Dawley rats. Ovx rats were implanted with cannulae in the 3rd ventricle of the hypothalamus and injected with either rAAV-Lep or rAAV-GFP (control vector encoding green fluorescent protein) and maintained for 10 weeks. Additional controls consisted of ovary-intact rats and ovx rats pair-fed to rAAV-Lep rats. Lumbar vertebrae were analyzed by micro-computed tomography and tibiae by histomorphometry. Cancellous bone volume was lower and osteoclast perimeter, osteoblast perimeter, and bone marrow adipocyte density were greater in ovx rats compared to ovary-intact controls. In contrast, differences among ovx groups were not detected for any endpoint evaluated. In conclusion, whereas estrogen deficiency resulted in marked cancellous osteopenia, increased bone turnover and marrow adiposity, increasing hypothalamic leptin transgene expression in ovx rats had neither detrimental nor beneficial effects on bone mass, architecture, or cellular endpoints. These findings demonstrate that the antiresorptive effects of subcutaneous leptin administration in ovx rats are mediated through leptin targets in the periphery.

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Section: Discussionsupporting

confidence: 92%

Effects of increased hypothalamic leptin gene expression on ovariectomy-induced bone loss in rats

et al. 2011

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“…The initial increase in energy intake in rAAV-GFP-treated rats following vector administration likely represents a rebound in food consumption following a surgery-induced reduction in food intake. In support, historical data indicate that age-matched ad lib- fed rats consume ~18 g/d of diet (Iwaniec, et al 2011). In contrast, an attenuated rebound in food intake was apparent in rAAV-Leptin treated rats.…”

Section: Discussionmentioning

confidence: 67%

Hypothalamic leptin gene therapy reduces body weight without accelerating age-related bone loss

Turner

Dube

Branscum

et al. 2015

Journal of Endocrinology

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Excessive weight gain in adults is associated with a variety of negative health outcomes. Unfortunately, dieting, exercise, and pharmacological interventions have had limited long-term success in weight control and can result in detrimental side effects, including accelerating age-related cancellous bone loss. We investigated the efficacy of using hypothalamic leptin gene therapy as an alternative method for reducing weight in skeletally-mature (9-month-old) female rats and determined the impact of leptin-induced weight loss on bone mass, density, and microarchitecture, and serum biomarkers of bone turnover (CTx and osteocalcin). Rats were implanted with cannulae in the 3rd ventricle of the hypothalamus and injected with either recombinant adeno-associated virus encoding the gene for rat leptin (rAAV-Leptin, n=7) or a control vector encoding green fluorescent protein (rAAV-GFP, n=10) and sacrificed 18 weeks later. A baseline control group (n=7) was sacrificed at vector administration. rAAV-Leptin-treated rats lost weight (−4±2%) while rAAV-GFP-treated rats gained weight (14±2%) during the study. At study termination, rAAV-Leptin-treated rats weighed 17% less than rAAV-GFP-treated rats and had lower abdominal white adipose tissue weight (−80%), serum leptin (−77%), and serum IGF1 (−34%). Cancellous bone volume fraction in distal femur metaphysis and epiphysis, and in lumbar vertebra tended to be lower (p<0.1) in rAAV-GFP-treated rats (13.5-months-old) compared to baseline control rats (9-months-old). Significant differences in cancellous bone or biomarkers of bone turnover were not detected between rAAV-Leptin and rAAV-GFP rats. In summary, rAAV-Leptin-treated rats maintained a lower body weight compared to baseline and rAAV-GFP-treated rats with minimal effects on bone mass, density, microarchitecture, or biochemical markers of bone turnover.

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“…This conclusion is supported by studies demonstrating that increasing leptin levels by sc administration of the hormone, direct delivery of the hormone into the hypothalamus, or by hypothalamic leptin gene therapy reduces MAT in ob/ob mice (Bartell et al 2011; Turner, et al 2015). However, ovx rats and normal mice fed high fat diet have elevated MAT in spite of elevated leptin levels, and increasing hypothalamic leptin levels does not decrease MAT in normal and ovx rats (Iwaniec, et al 2011; Jackson, et al 2011; Martin and Zissimos 1991). This paradox is resolved if, similar to appetite and weight gain, the inhibitory effects of high levels of leptin on MAT are impaired by development of leptin resistance (Sainz, et al 2015).…”

Section: Discussionmentioning

confidence: 90%

Role of estrogen receptor signaling in skeletal response to leptin in female ob/ob mice

Turner

Philbrick

Kuah

et al. 2017

Journal of Endocrinology

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Leptin, critical in regulation of energy metabolism, is also important for normal bone growth, maturation and turnover. Compared to wild type (WT) mice, bone mass is lower in leptin-deficient ob/ob mice; osteopenia in growing ob/ob mice is due to decreased bone accrual, and is associated with reduced longitudinal bone growth, impaired cancellous bone maturation and increased marrow adipose tissue (MAT). However, leptin deficiency also results in gonadal dysfunction, disrupting production of gonadal hormones which regulate bone growth and turnover. The present study evaluated the role of increased oestrogen in mediating the effects of leptin on bone in ob/ob mice. Three-month-old female ob/ob mice were randomized into one of 3 groups: (1) ob/ob+vehicle (veh), (2) ob/ob+leptin (leptin), or (3) ob/ob+leptin and the potent oestrogen receptor antagonist ICI 182,780 (leptin+ICI). Age-matched WT mice received vehicle. Leptin (40 μg/mouse, daily) and ICI (10 μg/mouse, 2x/w) were administered by sc injection for 1 month and bone analyzed by x-ray absorptiometry, microcomputed tomography, and static and dynamic histomorphometry. Uterine weight did not differ between ob/ob mice and ob/ob mice receiving leptin+ICI, indicating that ICI successfully blocked the uterine response to leptin-induced increases in oestrogen levels. Compared to leptin-treated ob/ob mice, ob/ob mice receiving leptin+ICI had lower uterine weight, did not differ in weight loss, MAT, or bone formation rate, and had higher longitudinal bone growth rate and cancellous bone volume fraction. We conclude that increased oestrogen signaling following leptin treatment is dispensable for the positive actions of leptin on bone and may attenuate leptin-induced bone growth.

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Hypothalamic leptin gene therapy prevents weight gain without long-term detrimental effects on bone in growing and skeletally mature female rats

Cited by 22 publications

References 95 publications

Effects of increased hypothalamic leptin gene expression on ovariectomy-induced bone loss in rats

Effects of increased hypothalamic leptin gene expression on ovariectomy-induced bone loss in rats

Hypothalamic leptin gene therapy reduces body weight without accelerating age-related bone loss

Role of estrogen receptor signaling in skeletal response to leptin in female ob/ob mice

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